The present invention relates to compounds for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 15-fluoro analogs of F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage, and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure (xe2x80x9cIOPxe2x80x9d) can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the flow of aqueous humor out of the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects, such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Some beta-blockers have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics may cause tachycardia, arrhythmia and hypertension. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
Prostaglandins, which are metabolite derivatives of arachidonic acid, have recently been pursued for possible efficacy in lowering IOP. Arachidonic acid in the body is converted to prostaglandin G2, which is subsequently converted to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering effects similar to those exhibited by PGF2xcex1 (an F-series prostaglandin): 
The relationship of PGF2xcex1 receptor activation and IOP lowering effects is not well understood. It is believed that PGF2xcex1 receptor activation leads to increased outflow of aqueous humor. Regardless of mechanism, PGF2xcex1 and analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F2xcex1 the Human Eye, Graefe""s Archive Ophthalmolog, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F2xcex1-1-Isopropylester Lowers Initraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF2xcex1 analogs with IOP lowering efficacy.
Synthetic PGF2xcex1-type analogs have been pursued in the art (Graefe""s Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF2xcex1-type molecules lower IOP, many of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)).
Based on the foregoing, a need exists for the development of molecules that may activate PGF2xcex1 receptors, yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
An agent which exhibits the same or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGF2xcex1, and methods of their use. It has now unexpectedly been discovered that the presently claimed 15-fluoro analogs of PGF2xcex1 meet this objective. While some prostaglandins with fluorine in the omega chain are known in the art [EP 435,443 A; JP 7,070,054 A2; Eksp. Klin. Farmakol., volume 57, number 2, pages 39-41 (1994) (Chemical Abstracts, volume 121, abstract 50656 (1994)); Izv. Akad. Nauk SSSR. Ser. Biol., volume 6, pages 831-7 (1989) (Chemical Abstracts, volume 112, abstract 30749 (1990))], the novel compounds of the present invention and their favorable therapeutic profiles in the treatment of glaucoma are neither disclosed nor suggested in that art.
The present invention is directed to compositions and methods of their use in treating IOP and ocular hypertension. In particular, the present invention provides 15-fluoro prostaglandin analogs believed to have functional PGF2xcex1 receptor agonist activity, and methods of their use in treating glaucoma and ocular hypertension. As previously stated, the mechanism of action by which PGF2xcex1 type prostaglandins lower IOP is not well understood. While the mechanism of action of the compounds of the present invention is not fully understood, the inventors theorize that such compounds exhibit enhanced FP receptor selectivity as a consequence of their decreased activity at the EP receptor site. While bound by no such theory, it is possible that an improved therapeutic index may result from a relative reduction of EP-mediated side-effects.
It has unexpectedly been found that 15-fluoro substituted PGF2xcex1 analogs of the present invention exhibit an improved therapeutic profile in the treatment of glaucoma and ocular hypertension when compared to natural prostaglandins and many of their known analogs. The substituted PGF2xcex1 analogs of the present invention have the following formula I: 
wherein:
R1=CO2R, CONR4R5, CH2OR6, or CH2NR7R8, where
R=H or cationic salt moiety, or CO2R=pharmaceutially acceptable ester moiety; R4,
R5=same or different=H or alkyl; R6=H, acyl, or alkyl; R7, R8=same or different=H, acyl, or alkyl; with the proviso that if one of R7, R8=acyl, then the other=H or alkyl;
n=0 or 2;
=single or non-cumulated double bond, with the provisos that a double bond between carbons 4 and 5 may not be of the trans configuration; and that a double bond between carbons 13 and 14 may not be of the cis configuration;
R2, R3=same or different=H, alkyl, or acyl;
D, D1=different=H and fluorine;
X=(CH2)q or (CH2)qO; where q=1-6; and
Y=a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or
Xxe2x80x94Y=(CH2)pY1; where p=0-6; and 
wherein:
W=CH2, O, S(O)m, NR9, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)m, CHxe2x95x90N, or CH2NR9; where m=0-2, and R9=H, alkyl, or acyl;
Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and
=single or double bond.
For purposes of the foregoing definition, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d means any ester that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and xe2x80x9cophthalmically acceptable esterxe2x80x9d means any pharmaceutically acceptable ester that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating. Preferred among the ophthalmically acceptable esters are alkyl esters. Most preferred are C2-C4 alkyl esters, and especially isopropyl esters.
Preferred for use in the methods and compositions of the present invention are those compounds of formula I above, wherein:
R1=CO2R, where R=H or CO2R=ophthalmically acceptable ester moiety;
n=0;
=single or non-cumulated double bond, with the provisos that a double bond between carbons 4 and 5 may not be of the trans configuration; and that a double bond between carbons 13 and 14 may not be of the cis configuration;
R2=R3=H;
D=fluorine in the alpha (xcex1) configuration, and D1=H in the beta (xcex2) configuration;
X CH2O or CH2CH2; and
Y=phenyl, optionally substituted with halo or trihalomethyl.
Especially preferred are those preferred compounds of formula I above, wherein:
R1=CO2R and CO2R=lower alkyl (i.e., 1-6 carbons) carboxylic acid alkyl ester. Included in these especially preferred compounds are the following novel compounds:
Included within the scope of the present invention are the individual enantiomers of the title compounds, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials (Asymmetric Synthesis by J. D. Morrison and J. W. Scott, Eds., Academic Press Publishers: New York, 1983-1985 (five volumes) and Principles of Asymmetric Synthesis by R. E. Gawley and J. Aube, Eds., Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC, G. Subramanian, Ed., VCH Publishers: New York, 1994; Chiral Separations by HPLC, A. M. Krstulovic, Ed., Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution or even mixing samples having different enantiomeric ratios.
In the foregoing illustrations, as well as those provided hereinafter, wavy line attachments indicate either the alpha (xcex1) or beta (xcex2) configuration. The carbon numbering is as indicated in the structural depiction of formula I, even when n=2. A hatched line, as used e.g. at carbon 9, indicates the a configuration. A solid triangular line, as used e.g. at carbon 12, indicates the xcex2 configuration. Dashed lines on bonds, e.g. between carbons 13 and 14, indicate a single or double bond. Two solid lines between carbons indicate a double bond of the specified configuration.